Oxygen has diverse applications in military operations and in clinical settings. While oxygen comprises 21% of the air that we breathe, human bodies are not adapted to higher levels of oxygen, and exposure to increased oxygen for an extended duration can be harmful. To minimize oxygen toxicity in clinical settings, the fractional inspired oxygen (FiO2) is typically titrated to maintain a hemoglobin saturation of >90% [4, 5]. However, there are clinical scenarios such as acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and refractory hypoxemia, in which a FiO2>60% may be required to prevent end-organ damage [3]. Additionally, it is not uncommon for pilots, divers, and astronauts to inhale high concentrations of oxygen prior to operations in order to reduce the risk of decompression sickness. In these scenarios, lung injury known as pulmonary oxygen toxicity (PO2T) may develop.
PO2T is a progressive disease defined clinically by acute tracheobronchitis, which manifests as cough and burning sensation with respiration, absorption atelectasis, pulmonary edema, acute parenchymal lung injury, and/or chronic lung injury [2]. Clinical signs include detrimental changes in vital capacity [6], lung compliance and diffusing capacity, radiographic evidence of non-cardiogenic edema, rales on auscultation, or a decreased ratio of arterial oxygen partial pressure (PaO2) to the FiO2. Histologically, PO2T is divided into two phases: the acute exudative phase (characterized by edema, hemorrhage, swelling and cellular destruction) and the chronic proliferative phase (transition to interstitial fibrosis and proliferation of type II alveolar epithelial cells) [7]. Unfortunately, by the time current diagnostic modalities detect injury, significant pulmonary damage has already occurred. Without a direct measure to identify PO2T, it is impossible to predict the point at which increasing lung injury is being sustained during oxygen administration.
Detecting PO2T early, and ameliorate or prevent PO2T will likely decrease mortality and shorten the length of hospitals stay that requiring the use of supplemental oxygen. In addition, detecting PO2T in operational settings will better guide operation decisions, and return to duty decisions allowing for improved military readiness. The lack of biomarkers to directly measure the early onset of PO2T represents significant gaps in this capability, and hinders the detection, diagnosis, and prevention/reduction of PO2T.
Breath analysis of specific volatile organic compounds (VOCs) has long been recognized as a reliable technique for diagnosing certain medical conditions including tissue inflammation (e.g. asthma), immune responses (e.g. to cancer cells or bacteria), metabolic disorders (e.g. diabetes), digestive processes, liver and/or kidney disorders, gum disease, halitosis, and other physiological conditions [27]. To date, more than 3,000 VOCs have been detected in exhaled breath. Of these compounds, about 1% are likely to contain disease-specific VOCs, such as alkanes, isoprenes, benzenes and methyl alkanes. Gas chromatography-mass spectrometry (GC-MS) and absorption spectrometry have been employed to measure VOCs in exhaled breath samples, and to create a VOC profile.
Recent human and animal research has demonstrated that prior to the onset of clinical symptoms, hypoxia induced significant oxidative stress that overwhelms inherent antioxidant enzymes and leads to lipid peroxidation [8, 9]. To date, breath biomarker research in the setting of oxygen exposure is limited to two studies. Biomarkers were detected in as little as 30 minutes of hyperoxic exposure in otherwise asymptomatic individuals [12]. Similarly, significant changes in exhaled molecular profiles of five VOCs were observed after submerged oxygen diving (Va Pojj et al. Respiratory physiology. 2014). However, no correlation has been reported between the presence of these VOCs, and relevant clinical endpoints of onset of PO2T, which is the objective of this invention. This application discloses a novel set of volatile organic compounds (VOCs) that can be used as noninvasive biomarkers for the detection of onset of PO2T in reduction and prevention of pulmonary injury or PO2T and to guide safe clinical oxygen use.